A mechanistic understanding of cancer rests heavily upon the mutated genes. Mutated genes include the dominant oncogenes and recessive suppressor genes that are mutated somatically to drive tumorigenesis. Pancreatic cancer has historically been an unusually efficient system in which to identify the important mutated genes, creating a portfolio of discoveries to which our research group has contributed. This success is due in part to highly informative structural patterns of homozygous deletions as well as well-matched pairs of normal/tumor samples where the tumor cells are expanded as cell lines and xenografts to enrich them over the otherwise contaminating stromal cells. Important mutations are thus efficiently identified and then confirmed in the original tissues. We recently published high-throughput genetic analysis techniques that quickly accelerate this line of study. High-throughput sequencing techniques will need to be complemented by other complementary primary analyses as well as followup genetic studies based upon the findings from the primary analyses. Our specific aims will locate promising sites of new somatically mutated genes. Homozygously deleted genes will be specifically targeted and the maps integrated with the identified mutated genes. We will discern the recurrent patterns of somatic mutations having patterns of inactivating mutations (for the tumor-suppressor genes and genome-maintenance genes) and of activating mutations (for the oncogenes). This comprehensive approach will enable us to identify and better characterize the key signaling pathways mutated in tumorigenesis. Our long-term goal is to provide a more complete foundation for future studies of tumorigenesis, disrupted signaling pathways, and therapeutic targets in pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a genetic disease caused by mutations. We identified frequent mutations in the p16, SMAD4, BRCA2, and other genes, and this line of research is now reaching a period of rapid development, for the advanced tools to explore these new mutations are now available.